Studying the miniscule cellular signals in heart failure

Topography, regulation and function of PDE-dependent cAMP nanodomains in cardiac myocytes (renewal)

Heart failure is a debilitating condition that often carries a poor prognosis. We know that a molecule in heart cells, called cAMP, is a lynchpin in several processes that go awry in heart failure. In fact, some current medicines already target signalling pathways that involve cAMP. However, the drugs don’t work well in everyone and we don’t know why – revealing the limitations of our understanding of cAMP in heart failure. This grant provides Professor Zaccolo with funding to continue her examination of cAMP signalling in the failing heart. In the previous funding period the team learned to apply state-of-the-art imaging to reveal cAMP signalling in heart cells. They discovered that heart cells function correctly only if multiple cAMP-related signals are generated simultaneously, and each signal is located within an extremely small space within the cell. Each minuscule signal is different and responsible for a specific effect. Now the team want to study how these tiny signals are generated, what function each of them regulates, how they work in a coordinated manner, and how these localised signals change in the diseased heart. They want to work towards a ‘precision medicine’ approach; targeting specific pools of cAMP within cells, to correct individual functions in heart failure.